The proposed research will test a novel mechanism for protecting higher cognition and reducing tau phosphorylation in the aging cortex, based on the unique needs of the newly evolved association cortical neurons most vulnerable in Alzheimer's Disease (AD). These circuits are powerfully modulated by feedforward, cAMP-PKA-calcium signaling, which becomes dysregulated with advancing age, leading to: 1) excessive opening of K+ channels, reducing neuronal firing and impairing cognition, and 2) phosphorylation of tau. Early stages of tau phosphorylation by PKA can be seen in aged rat association cortex, while more advanced stages are seen in aged monkey cortex, including fibrillated tau labeled by the AT8 antibody, and accompanying A? expression. The proposed research will test a strategy to regulate cAMP-PKA-calcium signaling to reduce AD- like pathology in the aging cortex by amplifying the brain's natural protective actions at glutamate metabotropic receptors type 3 (mGluR3). mGluR3 have neuroprotective actions on astrocytes, and additional, regulatory actions on neurons. New data have revealed post-synaptic mGluR3 in prefrontal association cortex (PFC) that regulate cAMP-PKA-calcium signaling. The proposed research will enhance stimulation of mGluR3 by its endogenous ligand, NAAG (N-acetylaspartyl-glutamic acid), via inhibition of the enzyme that destroys NAAG, GCPII (glutamate carboxypeptidase II). GCPII inhibitors are under development for treating inflammatory disorders, with excellent tolerability and minimal side effects in phase I human testing. We will observe whether mGluR3 are positioned to regulate cAMP-PKA phosphorylation of tau in the primate entorhinal cortex (ERC) and PFC circuits most vulnerable in AD, and whether GCPII inhibition can restore neuronal firing, improve cognitive function, inhibit phosphorylation of tau, and reduce neuroinflammation in aged rats and monkeys. This work will confirm and extend the efficacy of two structurally distinct GCPII inhibitors, 2-MPPA and 2- PMPA, under development by the Johns Hopkins Drug Discovery group. Aim 1 will use dual immunoelectron microscopy to confirm that mGluR3 are correctly positioned to regulate cAMP-PKA phosphorylation of tau (pS214Tau) and AT8-labeled tau in aging ERC and PFC glutamatergic synapses. Aim 2 will test whether acute administration of 2-MPPA or 2-PMPA enhances memory-related PFC neuronal firing in aging monkeys by regulating cAMP-PKA opening of K+ channels, and whether systemic administration can improve cognition in aged rats and monkeys with minimal side effects. Aim 3 will test whether chronic treatment with an optimal dose of 2-MPPA produces sustained improvement in working memory, and reduces tau phosphorylation and neuroinflammation in aged rat and monkey association cortex. We will have the rare opportunity to see if chronic 2-MPPA treatment in aged monkeys reduces both fibrillated AT8-labeled tau, and A? expression. Preliminary data indicate that these agents produce very robust improvements in cognition with no evidence of side effects, encouraging a therapeutic strategy with feasible translational application.